1. Field of the Invention
This invention relates to new polycyclic compounds containing nitrogen, to methods of making the compounds, and to the use of certain of the compounds as tranquilizing agents and as analgesics.
2. Description of the Prior Art
There is no known art describing compounds of the type disclosed in this invention. The closest known art describes the following structures which lack one or more features of the compounds of the invention. ##STR3## SUMMARY OF THE INVENTION
This invention is a compound (A) of the formula ##STR4## wherein n is zero or 1;
R is hydrogen, lower alkyl or cycloalkylalkyl of 5-10 carbon atoms, with the proviso that when R is hydrogen n = zero; PA1 R.sup.1 and R.sup.2, independently, are hydrogen, lower alkyl, lower alkoxy, nitro, amino, hydroxyl or cyano, with the proviso that at least one of R.sup.1 and R.sup.2 is hydrogen; PA1 R.sup.3 and R.sup.4 individually are H, methyl or ethyl, with with the proviso that only one of R.sup.3 and R.sup.4 can be H; and PA1 9-methylanthracene PA1 9-ethylanthracene PA1 2,9-dimethylanthracene PA1 1,9-dimethylanthracene PA1 2,10-dimethylanthracene PA1 10-ethyl-1-methylanthracene PA1 1-methoxy-10-methylanthracene PA1 1,10-dimethylanthracene PA1 9-methyl-1-anthronitrile PA1 10-methyl-1-anthronitrile
(B) a pharmaceutically acceptable acid addition salt of (A) where n is zero.
Preferred are the compounds of structure I where n is zero.
Also preferred are those compounds where n is zero and R is cycloalkylmethyl.
Most preferred for their tranquilizing effect are those compounds where n is zero, R is cycloalkylmethyl, R.sup.1 and R.sup.2 and R.sup.3 are each hydrogen and R.sup.4 is methyl.
The compounds where R is other than hydrogen have been found to be tranquilizers for warm-blooded animals and this invention further includes compositions of such compounds with pharmaceutically acceptable inert carriers and to the use of an effective dose of these compounds to tranquilize warm-blooded animals.
The compounds wherein R is H are valuable intermediates for making other members of the class.
The term "lower alkyl" means an alkyl group of 1-4 carbon atoms, including branched alkyl groups.
The term "cycloalkyl group" is employed in the sense of a radical derived from a ring of --CH.sub.2 -- groups by removal of a hydrogen atom.
Compounds of structure I have the trans configuration at the 3a-12b ring fusion with respect to the 12b-hydrogen atom and the 13-methano bridge (or in the alternative, and equivalent thereto, the five-membered nitrogen-containing ring is fused trans to the seven-membered ring). In accordance with usual chemical practice, structure I includes the dl-racemic mixtures as well as the d- and l- optical antipodes of the compounds of the invention.
The compounds of the invention can be made by a rearrangement reaction of bridged ethenoanthracenes.
These latter compounds are made by an internal Diels-Alder reaction of propargyl-substituted 9-anthracene-methylamines, and, in the case of compounds where R.sup.3 = methyl or ethyl and R.sup.4 = hydrogen, alternatively by internal Diels-Alder reaction of propargyl-substituted-9-anthracenemethyleneimines and 9-anthramides as disclosed in the commonly assigned, copending application Ser. No. 511,026, filed Sept. 30, 1974.
In one procedure for the preparation of compounds where R.sup.4 = H a substituted anthracene ##STR5## where R.sup.1 or R.sup.2 can be hydrogen, lower alkyl, lower alkoxy, nitro or cyano groups and R.sup.3 is methyl or ethyl, is reacted with oxalyl chloride in the presence of a catalyst to obtain the corresponding 9-anthroyl chloride. The substituted 9-anthroyl chloride is reacted with propargylamine per se or substituted on the nitrogen atom with the aforesaid R groups. These compounds undergo an internal Diels-Alder reaction to give substituted, 9,12-bridged ethenoanthracenes according to the equation. ##STR6##
This process can be carried out by heating the alkynylanthramide, either neat or in a suitable inert solvent, preferably an aromatic hydrocarbon, at a temperature of 80.degree. to 250.degree. C for a time sufficient to effect cyclization, generally from 1 to 48 hours depending on the conditions.
Reaction of II with bromine leads to a ring rearrangement reaction to produce products with the skeletal structure of I (stereochemistry unknown) substituted with bromine at the 12b and 13 positions, and containing a 1-carbonyl group. Bromination may be carried out in any inert solvent, preferably a chlorinated aliphatic hydrocarbon with methylene chloride and chloroform being especially preferred. The reaction temperature should be from about -20.degree. C to 100.degree. C, preferably 20.degree.-35.degree. C.
The bromine atoms are readily removed from the intermediate by reductive dehalogenation with a trialkyltin hydride, either neat, or dissolved in an aromatic hydrocarbon solvent. It is preferred to use tributyltin hydride in benzene or toluene. The reaction is carried out at a temperature in the range of 50.degree.-180.degree. C to give compounds having the trans skeletal structure of I which contain a 1-carbonyl group.
Alternatively the bromine atoms can be removed by reaction with zinc and acetic acid at 25.degree. to 120.degree. or with zinc and aqueous dimethylformamide.
The amides containing the 1-carbonyl group are readily converted to the corresponding amines of structure I by reduction of the carbonyl group, preferably with diborane dissolved in an ether solvent such as tetrahydrofuran, at a temperature of 0.degree.-100.degree. C.
Another procedure is to start with an ethenoanthracene of the formula ##STR7## which can be prepared from the corresponding 10-alkyl-9-anthraldehyde or 10-alkyl-9-anthracenemethyl iodide by reaction with propargylamine, followed by internal Diels-Alder reaction, reduction of the carbon-nitrogen double bond (where the starting material is a 10-alkyl-9-anthraldehyde), and alkylation of III(R=H) to obtain the derived N-substituted compound. Alternatively, III(R=H) may be acylated by conventional procedures, and the acyl derivatives may then be reduced with lithium aluminum hydride to obtain the corresponding N-substituted compounds.
In a preferred process for the preparation of III shown in the following equations, the 10-alkyl-9-anthraldehyde compound is reacted with a suitable amine at 25.degree. to 150.degree. in an alcohol solvent to form an imine. The imine is then reduced with a metal hydride reducing agent such as sodium borohydride or sodium cyanoborohydride in an alcohol such as methanol, ethanol, or isopropanol, which can be the same solvent that is employed to form the imine, at a temperature between 0.degree. and 100.degree. C. The resultant secondary amine is then condensed with a propargyl halide, preferably propargyl bromide, in the presence of an inorganic base such as an aqueous solution of an alkali metal carbonate or an organic base which does not react substantially with propargyl bromide, e.g., certain hindered amines including diisopropylethylamine, at a temperature of 0.degree. to 100.degree. C, preferaby at ambient temperatures.
The alkynyl-substituted anthracenes are then cyclized to compounds of Formula III as described hereinabove for the cyclization of the alkynylanthramides. ##STR8##
Ring rearrangement of bridged ethenoanthracenes (III) occurs in the presence of strong acids such as p-toluene-sulfonic acid and trifluoroacetic acid at about 70.degree. to 200.degree. C to give products having the skeletal structure of compound I but containing a double bond in the 1-12b position. The rearrangement is preferably carried out with trifluoroacetic acid. This reagent may also be employed for the rearrangement of compounds of structure III wherein R is an acyl group.
The double bond can be reduced to produce the desired trans structure at the 3a-12b carbon atoms by such reagents as sodium cyanoborohydride in acetic acid or by catalytic hydrogenation with a palladium catalyst in acetic acid solvent, or a platinum or rhodium catalyst in tetrahydrofuran. Reduction with a palladium catalyst in tetrahydrofuran gives a mixture of cis and trans racemates. The carbonyl group of the ring rearrangement product of III, R = acyl, must be reduced, e.g., with lithium aluminum hydride, before reduction of the 1-12b double bond to obtain the desired 3a-12b trans products. All of the above reductions are conveniently run at ambient temperatures, but temperatures between 0.degree. C and 60.degree. C are suitable. When catalytic hydrogenation is employed, the pressure of hydrogen should be from about 1 to about 10 atmospheres.
In this method R must be other than H and R.sup.1 and R.sup.2 can be hydrolytically stable groups. Hydroxyl-substituted compounds of structure I are obtained by cleavage of the corresponding alkoxy compounds, and amino compounds are obtained by reduction of the corresponding nitro compounds. Conventional aromatic nitration reactions of I (R.sup.1, R.sup.2 = H) can be employed for preparation of nitro derivatives. Additionally, hydroxyl derivatives can be obtained by diazotization of the amino compounds followed by hydrolysis.
Examples of known anthracenes which can be employed as starting materials to produce compounds where R.sup.4 is hydrogen include:
Compounds of structure I wherein R is hydrogen can be alkylated or acylated according to conventional procedures. The acyl derivatives may then be reduced with lithium aluminum hydride to obtain the corresponding N-substituted compounds, for example cycloalkylmethyl groups may be introduced onto the nitrogen atom by acylation with a cycloalkanecarbonyl chloride followed by reduction of the carbonyl group.
A process for the preparation of compounds where R.sup.4 is methyl or ethyl and R.sup.3 is H, Me or Et is shown in the following equations. .alpha.-Methyl-9-anthracenemethylenimine [Martynoff, Bull. Soc. Chim. France, 164 (1958)] is reduced with a metal hydride such as sodium cyanoborohydride in an alcohol such as methanol or ethanol, preferably in the presence of an organic acid such as acetic acid, at a temperature between 0.degree. and 100.degree.. The resultant primary amine is then condensed with a propargyl halide, preferably propargyl bromide, in the presence of an inorganic base such as an aqueous solution of an alkali carbonate or hydroxide, or an organic base which does not react substantially with propargyl bromide, e.g., certain hindered amines including diisopropylethylamine, at a temperature of 0.degree.-100.degree., preferably at ambient temperature. The N-propargylamine so obtained is then cyclized by heating, either neat or in a suitable solvent, preferably an aromatic hydrocarbon, at a temperature of 80.degree.-250.degree. for a time sufficient to effect cyclization. The process scheme may be depicted as follows: ##STR9##
The 1-methyl-1,2,3,5-tetrahydro-5,9b-o-benzeno-benz[e]isoindole so obtained is then alkylated or acylated by conventional procedures and the acyl derivatives reduced with lithium aluminum hydride to obtain the corresponding amines. Ring rearrangement of these amines is effected as described for compounds III above. Reduction of the 1-methyl-2,3-dihydro-8H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrro les so obtained may be effected by such reagents as sodium cyanoborohydride in acetic acid or by catalytic hydrogenation with a palladium catalyst in acetic acid solvent. Depending on the methods used, mixtures containing varying amounts of isomers A and B are obtained. Isomers A and B differ in the steric relationship of the 1-methyl group to the 3a,8-methano bridge (either syn or anti).
Use of .alpha.-ethyl-9-anthracenemethylenimine as the starting material in the above process leads to compounds where R.sup.4 = ethyl. Reaction of 10-methyl or 10-ethyl-9-anthracenecarbonitrile with methylmagnesium iodide gives 10-methyl or 10-ethyl-.alpha.-methyl-9-anthracenemethylenimine which, when carried through the above process, gives 8-methyl or 8-ethyl-2-alkyl-1-methyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6 ,7]cyclohepta[1,2-c]pyrroles.
In general, the 8, 3a and 12b carbon atoms are asymmetric carbon atoms. Depending on the method of synthesizing the compounds of this invention, there are obtained mixtures of racemates, pure racemates or optical antipodes.
The pharmacologically active compounds of the invention are trans at the 3a-12b ring fusion with respect to the 12b-hydrogen atom and the 13-methano bridge as depicted in structure I. The sterochemistry of the 3a-12b ring fusion was inferred from the crystal structure of the methiodide salt of the compound of structure I, R.sup.3 =H R.sup.4 =H, R=CH.sub.3, R.sup.1 =R.sup.2 =H, prepared by the preferred process of the invention as described above starting with 9-anthraldehyde. Crystals of this compound are monoclinic, space group P2.sub.1 /c, with cell dimensions of a = 10.219 .+-. 0.008, b = 14.759 .+-. 0.026, c = 12.902 .+-. 0.012A, and .beta.=100.64 .+-. 0.06.degree.. The C(1)C(12b)C(3a)C(13) torsion angle is -80.6 .+-. 1.0.degree. and the HC (12b)C(3a)C(13) torsion angle is 162.2 .+-. 5.0.degree. where H is the hydrogen on C(12b). The C(1)C(12b)C(3a)C(13) torsion angle is the angle between the C(12b)-C(1) and C(3a)-C(13)bonds in the C( 12b)-C(3a) projection (clockwise positive). These data establish that the 3a-12b ring fusion is trans with respect to the 12b-hydrogen atom and the 13-methano bridge. ##STR10##
Mixtures of racemates can be separated into the stereoisomeric pure racemates (diasterioisomers) by the use of known physical procedures, e.g., by chromatography or fractional distillation. Pure racemates can be separated into the optical antipodes by conventional methods such as combination with an optically active acid followed by separation by physical means such as recrystallization of the resultant salts.
Reduction with sodium cyanoborohydride, catalytic hydrogenation with Pd in acetic acid, or with Pt or Rh in tetrahydrofuran described above yields the desired trans structure at the ring junction 3a-12b.
The amine compounds of the present invention can be converted to the amine oxides by oxidation of the parent amine with hydrogen peroxide, peracetic acid, perbenzoic acid or the like at ambient temperature or between about 20.degree. C and 60.degree. C.
The amine or amine oxides can be used as such; however, in the case of the amines, addition salts of the active compound with pharmaceutically acceptable acids can be used for administration to warm-blooded animals alone or with an inert carrier. Such salts include hydrochlorides, sulfates, nitrates, phosphates, acetates, tartrates, citrates, lactates, maleates and fumarates of the amine compounds of this invention. The salts can be made, and the free bases can be recovered from the salts, by conventional methods including the use of ion exchange resins, metathetical reactions and the like.